Despite major advances in the medical and surgical management of atherosclerosis and its complications, atherothrombotic diseases (including myocardial infarction, stroke, and peripheral vascular disease) still cause significant morbidity and mortality. Identification of new targets and development of novel therapies directed at new and existing targets are needed to achieve further decrements in the morbidity and mortality of atherosclerosis. This proposal is focused on testing the central hypothesis that urokinase plasminogen activator (uPA), expressed by artery wall macrophages, contributes to the progression and complications of atherosclerosis. The proposal also applies insights derived from investigations of the mechanisms of uPAaccelerated atherosclerosis to design and express a uPA molecule that would be a highly effective local antithrombotic agent but would not accelerate atherosclerosis. There are 3 specific aims: (1) To test the hypothesis that macrophage-expressed uPA accelerates atherosclerosis by receptor-dependent activation of plasminogen. This aim will be accomplished by introducing a macrophage-targeted uPA transgene into mice that are deficient in plasminogen or the uPA receptor. (2) To test the hypotheses that macrophage-expressed uPA is atherogenic at low as well as high levels in Apoe-/- mice, and that atherosclerotic plaque rupture can be caused by elevated uPA expression in macrophages in advanced atherosclerotic lesions. This aim will be accomplished by using bone marrow transplantation to manipulate uPA expression in mouse macrophages. (3) To test the hypothesis that increased expression of uPA in the artery wall causes vasoconstriction, intimal growth, and lumen loss due to uPA receptor (uPAR)-dependent proteolytic activity and that these pathologic effects can be avoided by expression of a uPA mutant that is anchored to the endothelial cell surface. This aim will be accomplished using adenovirus-mediated gene transfer of wild-type and mutant uPA to the rabbit carotid artery. By understanding the mechanisms through which uPA accelerates atherosclerosis, we expect to obtain insights that will permit the design and development of targeted therapies that slow the progression of atherosclerosis, prevent plaque rupture, and inhibit intravascular thrombosis.